Molecular mechanisms of excessive alcohol consumption and relapse-like behavior

过量饮酒和复发样行为的分子机制

基本信息

批准号：
8335515
负责人：
Reginald DeVon Cannady
金额：
$ 2.94万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8335515
关键词：
Acids Address Alcohol consumption Alcohol dependence Alcoholism Alcohols Amino Acids Amygdaloid structure Behavior Behavioral Brain Brain region Cues Data Dependence Excitatory Synapse Glutamates Goals Heavy Drinking Immunohistochemistry Ion Channel Lead Light Maps Mediating Molecular Neurotransmitter Receptor Neurotransmitters Nucleus Accumbens Phosphorylation Post-Translational Protein Processing Pre-Clinical Model Predisposition Process Property Public Health Rattus Receptor Signaling Recording of previous events Relapse Rewards Rodent Model Role Self Administration Self-Administered Signal Transduction Site Specificity Stimulus Sucrose Synapses Techniques Testing Training Work addiction alcohol cue alcohol exposure alcohol reinforcement alcohol relapse alcohol seeking behavior alcohol use disorder alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid aniracetam calmodulin-dependent protein kinase II chronic alcohol ingestion drinking drinking behavior experience immunoreactivity inhibitor/antagonist insight neuroadaptation novel receptor reinforcer research study response reward processing synaptic function

项目摘要

The behavioral and molecular mechanisms underlying excessive alcohol drinking behavior and relapse are not fully understood and are vital for mapping the pathological course of alcoholism/dependence. Recent evidence indicates that chronic alcohol consumption leads to strengthening of excitatory synapses in key limbic brain regions that mediate reward and drinking behavior. This strengthening of synapses is highly dependent on the actions and synaptic incorporation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs); fast action ion channel receptors that are activated by the excitatory neurotransmitter glutamate. However, the mechanistic role of enhanced AMPAR signaling in alcohol reinforcement and alcohol-seeking behavior remains unclear. Thus, the proposed experiments in this application seek to elucidate the behavioral and molecular mechanisms that underlie AMPAR-mediated increases in operant alcohol-self-administration and potentiated relapse-like behavior using a preclinical model of high alcohol consumption, the alcoholpreferring (P-) rat. Preliminary data indicate that enhancement of AMPAR signaling by pretreatment with aniracetam (positive allosteric modulator of AMPARs), increases operant alcohol self-administration and potentiates cue-induced reinstatement to alcohol seeking in P-rats, suggesting that enhanced AMPAR activity may be critical in facilitating increased drinking and susceptibility to relapse. Experiments will further characterize the role of enhanced AMPAR signaling in modulating operant self-administration and relapse-like behavior. AMPAR activity can be potentiated by post-translational modification (e.g. phosphorylation of the AMPAR GluR1 subunit amino acid residue 831;pGluR1{831}). Using immunohistochemistry techniques, experiments will map neuroadaptive changes in pGluR1{831} subunits in limbic brain regions after a history of alcohol self-administration or exposure to an alcohol-related cue during cue-induced reinstatement to determine brain regions that may influence enhanced AMPAR-mediated increases in self-administration and alcohol-seeking. We predict to see changes in pGluR1{831} in the nucleus accumbens (self-administration studies) or amygdala (reinstatement studies), and these regions will be targeted to investigate functional neuroanatomical control of enhanced AMPAR activity-mediated facilitation of alcohol self-administration and seeking behavior using aniracetam. Control experiments will address neuroanatomical and reinforcer specificity and non-specific locomotor effects. Lastly we will determine if aniracetam-induced increases in alcohol self-administration and seeking behavior are dependent on Ca2+/calmodulin-dependent protein kinase II (CamKII; known to phosphorylate GluR1 and enhance AMPAR activity) by blocking aniracetam-induced effects during self administration and reinstatement sessions with KN93 (CamKII inhibitor). Key findings from these studies will provide novel insight into AMPAR-related mechanisms in excessive alcohol drinking behavior and vulnerability to relapse.

过度酒精饮酒行为和复发的行为和分子机制尚未完全理解，对于绘制酒精中毒/依赖性的病理过程至关重要。最近的证据表明，长期饮酒会导致在关键的边缘大脑区域中加强兴奋性突触，从而介导奖励和饮酒行为。突触的加强高度取决于α-Amino-3-羟基-5-甲基-4-异沙唑二酸受体（AMPARS）的作用和突触掺入；快速作用离子通道受体被兴奋性神经递质谷氨酸激活。但是，增强AMPAR信号在酒精加强和寻求酒精的行为中的机理作用尚不清楚。因此，该应用中提出的实验旨在阐明AMPAR介导的能型酒精自身给药的增加的行为和分子机制，并使用高酒精消耗的临时性模型，即酒精饮用（P-）大鼠，并增强了类似复发的行为。初步数据表明，通过使用AniraceTam（AniraceTam阳性变构调节剂）预处理AMPAR信号传导，增加了饮酒自我给药，并增强了提示在P-大鼠中恢复对酒精的恢复，这表明增强的Ampar活性可能对促进饮酒的增强可能至关重要。实验将进一步表征增强AMPAR信号传导在调节操作者自我给药和复发样行为中的作用。 AMPAR活性可以通过翻译后修饰（例如AMPAR GLUR1亚基氨基酸残基831; PGLUR1 {831}的磷酸化）增强。 Using immunohistochemistry techniques, experiments will map neuroadaptive changes in pGluR1{831} subunits in limbic brain regions after a history of alcohol self-administration or exposure to an alcohol-related cue during cue-induced reinstatement to determine brain regions that may influence enhanced AMPAR-mediated increases in self-administration and alcohol-seeking.我们预测，在Accumbens（自我管理研究）或杏仁核（恢复生长研究）中，PGLUR1 {831}的变化，这些区域将旨在调查对AMPAR活性促进使用An-Ardiministration Anniriracetam的促进AMPAR活性促进的功能性神经解控制。控制实验将解决神经解剖学和增强剂特异性以及非特异性运动效应。最后，我们将确定aniracetam诱导的酒精自我给药和寻求行为是否取决于Ca2+/钙调蛋白依赖性蛋白激酶II（CAMKII；已知为磷酸化GLUR1磷酸化并增强AMPAR活性并增强AMPAR活性），从而通过使用AniracetAm诱导的对使用kn93进行了自我施用和抑制kn93（CAMKITITER）的影响。这些研究的主要发现将为过度饮酒行为和复发脆弱性的AMPAR相关机制提供新的见解。